Cryptosporidiosis

Cryptosporidium spp are tiny intracellular protozoan parasites that infect the gastrointestinal epithelium of vertebrates. Most human infections are caused by Cryptosporidium hominis and Cryptosporidium parvum and mainly affect immunocompromised individuals or immunocompetent children younger than 5. Cryptosporidium is widespread in the developing world. Oral ingestion of an infectious dose of oocysts results in the formation of sporozoites in the intestinal lumen. Sporozoites subsequently attach to the intestinal epithelium, triggering elongation and fusion of epithelial cell microvilli enclosing the sporozoite within a vacuole. Sporozoites then develop into merozoites, which replicate and invade neighboring cells. Cryptosporidium spp infection usually involves the small bowel. Enteric illness ranges from self-limiting diarrhea in immunocompetent hosts to severe prolonged enteritis refractory to treatment in immunocompromised individuals. The latter is the most common clinical feature of cryptosporidial infection in humans. Cryptosporidium spp infection may additionally involve the respiratory epithelium or the biliary tract. Clinical manifestations of cryptosporidiosis depend on the immune-status of the infected host. Cryptosporidium spp has especially been associated with chronic diarrhea, decreased quality of life, and shortened survival in HIV-infected patients. Morbidity from cryptosporidiosis has markedly decreased in the era of HAART but is still a problem in developing countries with limited access to this therapy.

Diagnosis is established by stool testing using specific stains, PCR or small bowel or rectal biopsies. Oocyts may be detected with a modified acid-fast stain of the stool, enzyme-linked immunosorbent assay (ELISA) or direct fluorescence antibody tests. Although there is some evidence for effectiveness of nitazoxanide, administered 500 mg twice daily until clinical symptoms resolve and oocysts are eliminated from the stool, there are currently no further data supporting the effectiveness of chemotherapeutic agents in the treatment of cryptosporidiosis in immunocompromised patients. Treatment should primarily comprise supportive management, including rehydration, electrolyte replacement, and antimotility agents. In HIV-infected patients, HAART is the most important treatment to improve the immune function and the CD4 counts.

Strongyloidiasis

Strongyloidiasis is a parasitic infection caused by the intestinal nematode Strongyloides . The most frequently found species pathogenic for humans, resulting in abdominal pain and diarrhea worldwide, is Strongyloides stercoralis , which is endemic to tropical and subtropical regions. After penetrating the skin and entering circulation, the filariform larvae proceed to the lungs, penetrate the alveoli, ascend the tracheobronchial tree and are subsequently swallowed. In the duodenum and jejunum, the larvae mature into adult females that produce up to 40 eggs per day, subsequently releasing the larvae into the intestinal wall. After migrating into the intestinal lumen, the larvae are passed into feces or mature into filariform larvae that infect the intestinal mucosa or perianal region. In immunocompromised patients (eg, immune deficiency, hematologic malignancies, administration of corticosteroids, HIV infection, diabetes, transplantation, advanced age), a hyperinfection syndrome, which is characterized by detection of increased number of larvae in stool, sputum, and tissue, may increase mortality. Half of the patients with Strongyloides infection are asymptomatic. However, the most common clinical manifestations are related to the gastrointestinal tract and mainly include unspecific symptoms, such as abdominal pain, diarrhea, vomiting, flatulence, and constipation. In advanced cases, paralytic ileus, small bowel obstruction, gastrointestinal bleeding, and protein-losing enteropathy may occur. In the larvae’s migration phase, respiratory symptoms ranging from coughing or wheezing to severe symptoms, such as dyspnea, pleuritic pain, or hemoptysis in case of hyperinfection syndrome, may be seen. Diagnostic tools include stool testing for ova and parasites, complete blood count to check for eosinophilia, ELISA for S stercoralis serology if available, sputum cultures in patients with pulmonary manifestations and suspected hyperinfection syndrome, and small bowel biopsy. The examination of duodenal biopsy specimens for ova and larvae is the most sensitive diagnostic procedure for S stercoralis . S stercoralis hyperinfection is a cause of severe illness in immunocompromised patients and should be especially considered in patients from areas where this infection is endemic. Treatment options for uncomplicated disease include ivermectin, thiabendazole, and albendazole alone or in combination. Ivermectin, a macrolide like agent that has become the drug of choice in strongyloidiasis, should be given at a dose of 200 μg/kg orally once a day for 1 to 2 days in patients with uncomplicated disease weighing more than 15 kg. If necessary, treatment may be repeated 2 to 3 weeks after the first course. In hyperinfection syndrome and disseminated disease, ivermectin is recommended to be administered daily until symptoms resolve and stool tests have been negative for at least 2 weeks. Thiabendazole at a dosage of 25 mg/kg orally twice a day for 3 days may be given as an alternative in complicated infection but has significant adverse events, such as dizziness, nausea, and abdominal pain. Albendazole, a broad-spectrum anthelmintic agent, at a dosage of 10 mg/kg/d for 7 days can be used as an alternative if the previous drugs are not available. However, there are limited data on treatment options for hyperinfection or disseminated disease with anthelmintic drugs.

Cytoisosporiasis (Formerly Known as Isosporiasis)

Infection with the protozoan Cytoisospora belli (formerly known as Isospora belli ) commonly runs a benign, asymptomatic, and self-limiting course in immunocompetent patients, whereas in immunocompromised hosts, symptoms may range from watery diarrhea, vomiting, abdominal pain, and weight loss to dehydration often requiring subsequent hospitalization. Cytoisospora belli is the only Cytoisospora protozoan infecting humans and commonly occurs in tropical and subtropical regions. Most of the cases have been reported in patients with AIDS and kidney or liver transplantation. Treatment options for Cytoisosporiasis include trimethoprim/sulfamethoxazole (160 mg/800 mg) given orally 4 times a day for 10 days as well as ciprofloxacin (500 mg) twice daily for 7 days as an alternative in case of allergy to sulphonamides.

Campylobacter spp

Bloodstream infection caused by Campylobacter is a rare condition and mainly occurs in patients with immune deficiency, hypogammaglobulinemia, HIV infection, malignancy, and solid organ transplantation. Before the era of HAART, advanced stage HIV disease was the most important underlying condition in Campylobacter bacteremia. Interestingly, Campylobacter bacteremia has been reported to have an extraintestinal origin in approximately 30% of the cases; however, the most common source of bacteremia is found intra-abdominal. Clinical characteristics include fever as the most common clinical symptom, followed by abdominal pain and diarrhea, as well as less frequent complaints such as respiratory symptoms and soft tissue damage.

Salmonella spp

Bloodstream infection with nontyphoid Salmonella infection has been reported in heart-transplant recipients. Cases of infection with nontyphoid Salmonella , foodborne pathogens causing gastroenteritis, bacteremia, and focal metastatic infection, have also been reported in patients after renal transplantation. Clinical presentation of nontyphoid Salmonella infection in solid-organ transplant recipients, including febrile enteritis and bloodstream infection, differs from that seen in immunocompetent hosts, where Salmonella usually causes nonfebrile gastrointestinal infection.

Chlamydia Trachomatis

Ulcerative rectocolitis mimicking the clinical picture of Crohn’s disease in HIV-infected patients may rarely also be caused by gut mucosal infection owing to lymphogranuloma venerum caused by serovars L1 to L3 of Chlamydia trachomatis, which is currently reemerging as a sexually transmitted disease. Diagnosis of bacterial diarrhea may easily be established by stool cultures and blood cultures owing to the high rate of bacteremia in these patients. Antimicrobial treatment should be administered according to identification of specific organisms by culture, as well as local resistance rates.

Mycobacterium spp

Mycobacterial infections with Mycobacterium tuberculosis and nontuberculous mycobacteria (eg, Mycobacterium avium ) may cause gastrointestinal infections presenting with diarrhea in HIV-associated immunosuppression. In contrast to infections with M tuberculosis , which rarely present with diarrhea, diarrhea it is a common feature in infections with members of the M avium complex. Disseminated M avium complex disease is the most common opportunistic bacterial infection in advanced stage AIDS. Although the rate of M avium complex infection has declined in the era of HAART, patients with low CD4 counts remain at an increased risk. Clinical presentation of M avium complex disease includes fever, weight loss, night sweats, fatigue, and watery diarrhea, usually without fecal white blood cells, malabsorption, lymphadenopathy, organomegaly, anemia, and elevated liver enzymes; however, all of these symptoms may also occur during the course of HIV infection either as a symptom of advanced stage HIV infection or with other opportunistic infections. Abdominal symptoms, such as pain and diarrhea, have been reported in one-fourth to one-third of patients with M avium complex disease. Gastrointestinal infection usually affects the upper gastrointestinal tract (eg, duodenum), which may be suggested at endoscopy by the presence of multiple raised mucosal nodules or yellowish patches ( Fig. 1 A). Less common endoscopic findings include ulceration, edema, erythema, aphthous lesions, or strictures. Diagnosis can be established by endoscopic biopsy. Small-bowel biopsies may show macrophages filled with acid-fast bacilli, similar to Whipple disease. M avium infection may also be revealed by blood and stool cultures, although stool cultures have not been suggested to be useful when blood cultures are negative. Preferred treatment regimens for disseminated M avium infection are (1) clarithromycin (500 mg twice daily) plus ethambutol (15 mg/kg once daily) with or without rifabutin (300 mg once daily), which has been shown to reduce mortality when added, or (2) azithromycin (500–600 mg once daily) plus ethambutol (15 mg/kg daily). Fluorochinolones (eg, moxifloxacin 400 mg once daily or levofloxacin 500–750 mg once daily) plus ethambutol plus rifabutin have been suggested for patients with clarithromycin-resistant M avium infection. Patients with CD4 counts less than 50 cells/mm ³ are at increased risk for M avium infection, and should receive chemoprophylaxis with azithromycin (1200 mg once per week) or clarithromycin (500 mg twice daily). Alternatively, rifabutin at a dosage of 300 mg once daily or azithromycin at dosages ranging from 500 to 600 mg once daily may be given. Prophylaxis can be stopped when CD4 counts increase to more than 100 cells/mm ³ .

Endoscopy of the duodenum of a patient with Mycobacterium avium infection with the presence of raised mucosal nodules and yellowish patches ( panel A ). Histology of mesenteric lymph nodes showing granulomas with central necrosis ( panel B ). HE stain, magnification 100×.

( Courtesy of Gregor Gorkiewicz, MD, Institute of Pathology, Medical University of Graz, Graz, Austria.)

Clostridium difficile

Clostridium difficile is a gram-positive spore-forming bacterium. Strains producing toxin A and/or toxin B can cause colitis and diarrhea. C difficile is a common nosocomial infection when hospital inpatients get infected with spores, which often contaminate the hospital environment and hands or instruments of health care workers. The spores of C difficile are resistant to alcohol-based disinfectants and can survive in the environment for up to 6 months. Risk factors for C difficile infection (CDI) are a previous antibiotic therapy altering the normal intestinal microbiota and its colonization resistance to pathogens, acid-suppressing drugs, especially proton pump inhibitors, advanced age, severe underlying diseases, surgery, and a previous chemotherapy. Immunocompromised hosts are more susceptible to infections with C difficile and have an increased risk for severe manifestations of this infection. The risk depends on the underlying disease, the mode of immunosuppression, and the environment. Hypervirulent C difficile strains like BI-NAP1-O27 can cause local epidemics in hospitals and are associated with an increased mortality from CDI. The reported rates of CDI in immunocompromised patients, for example in patients after solid organ transplantation, vary considerably. The incidence of CDI in these patients is, however, higher than in the normal population. The rate of CDI was 31% in recipients of lung transplants, about 4% in recipients of kidney transplants, 8% to 15% in recipients of kidney/pancreas transplants, and 3% in liver transplants. About 9% of patients after high-dose chemotherapy and autologous hematopoietic stem cell transplantation developed CDI. Because of frequent hospitalization and exposure to antibiotics, C difficile has been reported to be the most common bacterial pathogen causing infectious diarrhea in HIV-infected patients. Data on severity and recurrence of CDI in immunocompromised patients are inconclusive. In patients who had solid organ transplantation, there was no increased rate of complicated colitis or relapsing CDI as compared with patients who did not receive a transplant. However, the use of glucocorticoids was associated with an increased mortality in CDI and also an increased rate of relapsing CDI.

For many years, diagnosis for C difficile was routinely established using enzyme immunoassays for toxin A and/or toxin B. Although these assays provide results within a short time period and are easy to use, the sensitivity (70%–80%) for diagnosis of CDI is not as good as it has been previously assumed. The assay for the common antigen of C difficile is more sensitive; however, it also detects toxin-negative C difficile strains not causing disease. Currently, the toxigenic anaerobic culture seems to be the gold standard for diagnosis of CDI; however, it takes up to 72 hours to obtain a result. Recently, real-time PCR assays for the toxin genes of C difficile (tcd B, tcd A, tcd C) have been developed for a fast and reliable diagnosis of CDI and they appear to have good sensitivity and specificity.

CDI is treated by antibiotics directed against C difficile . Standard therapy is either oral metronidazole (500 mg 3 times a day for 10–14 days) or oral vancomycin (125–250 mg 4 times a day for 10–14 days). In severe forms of CDI or infections with the hypervirulent strain BI-NAP1-O27, vancomycin is superior compared with metronidazole with regard to treatment success and rate of relapses ; however, treatment with metronidazole is less expensive and therefore recommended in mild cases. In patients who are immunocompromised, vancomycin should be used as initial therapy. A new nonabsorbable antibiotic fidaxomicin (200 mg twice a day for 10 days) is at least as effective as vancomycin in CDI treatment and has fewer relapse rates. Monoclonal antibodies directed against toxin A and toxin B (single dose of 10 mg/kg body weight intravenously), in addition to antibiotic therapy, also reduce the rate of C difficile recurrence.

In recurrent disease, long-term vancomycin therapy (vancomycin pulse and taper) with or without Saccharomyces boulardii (500 mg twice a day) or rifaximin (400 mg 3 times a day for 14 days) following a course vancomycin has been shown to be effective. In treatment-refractory cases, the restoration of the altered colonic microbiome by fecal bacteriotherapy (installation of fresh stool of a healthy subject by colonoscopy or enema, “stool transplantation”) has been shown to be very effective.

Cytomegalovirus (CMV)

Gastrointestinal CMV disease usually occurs among immunocompromised individuals and particularly affects patients with HIV infection, solid organ or hematopoietic stem cell transplantation, or secondary immunodeficiency owing to corticosteroids, immunosuppressive treatment, or chemotherapy. Transmission of CMV, a DNA virus and member of the Herpesviridae family, usually occurs by close contact with bodily fluids (ie, urine, saliva, blood, tears, breast milk, vaginal fluids). It is clinically important to differentiate between CMV infection, referring to the detection of CMV antigens or antibodies without clinical features of tissue damage, and CMV disease, where CMV reactivation causes tissue damage with subsequent clinical symptoms. Because gastrointestinal CMV disease is a major cause of morbidity and mortality in immunocompromised patients, diagnosis at an early stage is essential and may be best confirmed by endoscopic biopsy and subsequent histologic analysis, including immunologic staining. Gastrointestinal CMV disease may affect any portion of the gastrointestinal tract, but usually presents as colitis with symptoms ranging from low-grade fever, weight loss, anorexia, and abdominal pain to bloody diarrhea. Fulminant colitis may occur as one of the most severe clinical afflictions. Colonoscopy is the preferred method to establish diagnosis. Endoscopic findings include patchy erythema, edema, erosions, and ulcerations.

The role of CMV in exacerbation of inflammatory bowel disease remains unclear. It is currently not established whether CMV worsens inflammation or merely is a surrogate marker for severe colitis. Because most patients with inflammatory bowel disease (IBD) are seropositive for CMV infection and have impaired natural killer cell activity and defects in mucosal immunity, CMV reactivation is a probable event during periods of intestinal inflammation. Moreover, immunosuppressive drugs enhance susceptibility to CMV reactivation. In patients with severe and/or steroid-refractory ulcerative colitis, local reactivation of CMV can be detected in approximately 30% of the cases, whereas CMV colitis rarely occurs in patients with Crohn disease or mild to moderate ulcerative colitis. Although one would expect worse prognosis in patients with steroid-refractive ulcerative colitis who have been tested positive for CMV, the presence of CMV in the colon of these patients has not been shown to be associated with disease activity, response to medications, or colectomy rate. In summary, local CMV reactivation might be seen as a secondary event in severe steroid-refractory colitis and does not seem to influence prognosis. Furthermore, there are insufficient data as to whether antiviral therapy affects colectomy and remission rates ; however, clinical recommendations include testing for CMV reactivation via leukocyte PCR or immunohistochemistry on colonic biopsy specimens in patients with severe steroid-refractive colitis as well as antiviral therapy (eg, ganciclovir, foscarnet) if colonic CMV is detected.

The most effective antiviral agents in CMV disease are ganciclovir (5 mg/kg intravenously twice daily for at least 3 weeks), an acyclovir derivate, valganciclovir (900 mg twice a day for at least 3 weeks), an oral analog of ganciclovir, and foscarnet (90 mg/kg intravenously twice daily for 3–6 weeks), a pyrophosphate analog inhibiting viral replication. Ganciclovir is the treatment of choice for CMV colitis, however. Foscarnet has the advantage of being less bone marrow suppressive compared with ganciclovir. The newest agent used for CMV disease (eg, CMV retinitis) is cidofovir (5 mg/kg once weekly for at least 2 weeks), which has to be administered intravenously, as is the case for ganciclovir and foscarnet. To our knowledge, however, there are no clinical studies on the use of cidofovir in CMV colitis.

Norovirus

In addition to common enteric viruses such as adenovirus and rotaviruses, norovirus, the most common cause of nonbacterial gastroenteritis worldwide, has been recently identified as an unsuspected cause of prolonged morbidity and mortality after chemotherapy and hematopoietic stem cell transplantation (HSCT). Norovirus, typically presenting with sudden onset of vomiting and diarrhea, was shown to cause life-threatening gastroenteritis in HSCT recipients and therefore should be considered as a possible infectious agent in the differential diagnosis of diarrhea in these patients. Three genogroups (I, II, IV) of noroviruses, belonging to the family of the Caliciviridae, are pathogenic for humans. In contrast to immunocompetent hosts, who usually have self-limiting symptoms only for a few days, norovirus infection has been reported to cause prolonged gastroenteritis and severe illness in immunocompromised children after intestinal transplantation or chemotherapy. Norovirus infection was furthermore shown to persist in adult renal allograft recipients and may present with or without clinical symptoms. Diagnosis is established from fecal samples by reverse-transcriptase PCR for norovirus RNA. Because no specific treatment is available, therapeutic management mainly includes symptomatic treatment, including intravenous fluid and electrolyte substitution, as well as enteral and total parenteral nutrition in protracted illness. Reduction of immunosuppressive medication may be considered in cases with severe symptoms and should be performed with great care. A potential role of treatment with oral human immunoglobulin has been recently suggested.

Histoplasmosis

Fungi such as Candida species can be frequently isolated from the stool of HIV infected patients. However, their role as a causative agent of HIV-associated diarrhea remains unclear. Disseminated infection with the dimorphic fungus Histoplasma capsulatum (Histoplasmosis), the most common endemic mycosis in HIV-infected patients, may affect the gastrointestinal tract of AIDS patients subsequently leading to diarrhea. The risk of developing histoplasmosis as well as the severity of illness increase as the CD4 counts decline. Fever and abdominal pain have been reported in approximately 70% of the patients with gastrointestinal histoplasmosis while weight loss and diarrhea have been reported in less than 50%. Gastrointestinal histoplasmosis often occurs in association with pulmonary and hepatic histoplasmosis and may affect the ileocaecal region.

The diagnosis of gastrointestinal histoplasmosis should be considered in HIV-infected patients with major complications such as gastrointestinal obstruction or bleeding, perforation, an abdominal mass, hepatosplenomegaly, or gastrointestinal symptoms accompanied by weight loss or fever. Diagnosis is established by stool cultures for fungi, culture of urine, blood, and bowel or other tissue specimens, serum and urine Histoplasma antigen testing or histopathologic examination of gastrointestinal tissue specimens. Treatment options for disseminated histoplasmosis include amphotericin B (3 mg/kg daily for 1–2 weeks) followed by oral itraconazole (200 mg 3 times daily for 3 days followed by 200 mg twice daily for at least 12 months). In HIV-infected patients with CD4 counts less than 150 cells/mm ³ in endemic areas, prophylaxis with itraconazole (200 mg daily) is recommended.

Microsporidiosis

Microsporidia are intracellular microorganisms that have recently been reclassified from protozoa to fungi. They result in emerging infections in patients with AIDS, organ transplant recipients, children, travelers, and elderly people. Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most important species leading to human infections. Most infections are caused by E bieneusi. In approximately half of the patients with AIDS suffering from chronic diarrhea, microsporidia may be identified as the causative organism. The prevalence of infection strongly correlates with decreasing CD4 counts and has markedly declined in the era of HAART. Clinical manifestations of microsporidiosis include chronic watery noninflammatory diarrhea, weight loss, abdominal pain, nausea, vomiting, fever, sclerosing cholangitis, and colitis. Diagnosis of microsporidia from stool samples by light microscopy is challenging because of their small size of 1 to 2 μm. Although time-consuming and labor-intensive, transmission electron microscopic examination on small bowel biopsy specimens to identify the polar filament and other species-specific ultrastructural characters remains the diagnostic gold standard. Additional diagnostic methods are light microscopy–based methods, including histologic stains, such as the modified trichrome stain, nucleic acid-based methods (PCR) from clinical samples (eg, tissue biopsies, stool, duodenal aspirates, urine specimens), antigen-based detection methods (eg, immunofluorescence assays, ELISA), and antibody-based detection methods. The only available antimicrobial treatment is albendazole (400 mg twice daily for 3 weeks), which is effective for E intestinalis . Similar to cryptosporidial infection, HAART is the best therapy for microsporidia infection.

Idiopathic AIDS Enteropathy

A unique entity called “idiopathic AIDS enteropathy” or “HIV enteropathy” can be diagnosed once identifiable infections as well as other causes of diarrhea have been excluded. Multiple factors, including an increase in inflammation and immune activation, as well as decreases in mucosal repair and regeneration, contribute to AIDS enteropathy. The gut-associated lymphoid tissue has been shown to play an important role as one of the early targets in HIV infection and severe CD4 cell depletion. In the early course of HIV infection, massive and progressive depletion of gastrointestinal effector memory CD4 T-lymphocytes results in failure to maintain the epithelial barrier function of the gut mucosa, subsequently enabling translocation of microbial products, such as lipopolysaccharide, peptidoglycans, and viral genomes. These microbial products lead to activation of the gastrointestinal and systemic immune system through stimulation of the innate immune system via Toll-like receptors; however, the resultant activated T cells are a further target for HIV. HIV enteropathy usually affects the jejunum and has been described to be associated with villus atrophy and crypt hyperplasia. In conclusion, “idiopathic AIDS enteropathy” or “HIV enteropathy” has emerged as a pathogen-negative diarrhea and may be seen as the result of undiscovered infectious pathogens, inflammatory changes within the gastrointestinal tract caused by HIV itself, other environmental or infectious agents, as well as a complex interplay among all these factors. This form of enteropathy improves with HAART and increasing CD4 counts.

Drug-induced diarrhea has become increasingly important as a cause of diarrhea in HIV-infected patients in the era of HAART. Diarrhea is a common side effect of HAART and often leads to discontinuation of antiretroviral therapy. Protease inhibitors are the most common agents associated with diarrhea as a side effect. Besides other undesirable side effects, such as metabolic or cardiovascular complications, protease inhibitors frequently cause gastrointestinal disorders ranging from mucosal erosions to epithelial barrier dysfunction and diarrhea. Although antimotility agents, such as loperamide, diphenoxylate, and codeine, as well as adsorbents (eg, bismuth subsalicylate) have been considered to be useful, there is lack of good evidence for symptomatic management of drug-induced diarrhea in HIV-infected patients. Therefore, no specific recommendation can be made.

Other Noninfectious Mechanisms

The neurotropic properties of HIV lead to a generalized autonomic neuropathy, therefore another suggested noninfectious mechanism of HIV-associated diarrhea is rapid intestinal transit owing to damage of the autonomic nervous system. Furthermore, diarrhea may be caused by HIV-associated malignancies, such as non-Hodgkin B-cell lymphoma and Kaposi sarcoma. Multiple effects of HIV infection (eg, opportunistic infections, HIV itself, HAART) may impair exocrine pancreatic function, which in turn leads to chronic diarrhea via fat malabsorption.